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IMPACT OF CONVENTIONAL MORPHOLOGICAL DIAGNOSIS
UPON THE PROGNOSIS AND THE THERAPY OF INVASIVE
BREAST CARCINOMA
V. FULGA, PhD, Associate professor
O. MAZURU, Assistant professor
V. DAVID, PhD, Associate professor
L. RUDICO, Assistant professor
V. MAZURU, PhD, Assistant professor
L. SAPTEFRATI, PhD, Associate professor
Department of Histology, Cytology and Embryology,
State University of Medicine and Pharmacy “Nicoale Testemitanu”,
Kishinev, Republic of Moldova
Histological examination is considered “golden standard” in tumors
diagnosis. Breast carcinoma is a heterogeneous entity that consists of
morphological subtypes, which in spite of common origin are very diverse
histologically and clinically. The highest heterogeneity is specific for ductal
invasive carcinoma, which is the most frequent diagnosed form of the breast
cancer. In order to elaborate an effective treatment there are taken in
consideration clinical criteria, such as age, lymph nodes state, tumor size, as
© V. Fulga, O. Mazuru, V. David, L. Rudico, V. Mazuru, L. Saptefrati, 2015
217
well as some histological peculiarities like histological grade, lymphovascular
invasion. Unfortunately, these parameters do not have a predictive potential
for the diverse types of therapies, applied in treatment of breast carcinoma.
The aim of this work was to review the prognostic and predictive potential of
morphological diagnosis in breast carcinoma.
Management of patients with breast carcinoma is still guided by clinicpathological and morphological features. Although some schemes of treatment
seem to be effective, there is no yet enough potential to realize a personalized
therapy. The blind treatment of breast carcinoma, based rather on the
statistics, in which the classical histological aspect of the tumor has only
prognostic value, being valueless from the predictive point of view was the
reason for a complex studying of a broad spectrum of cellular markers.
Вreast cancer, morphological classification, predictive potential,
prognostic value
The defining of tumor progression in breast carcinoma was not possible for
a long period of time, because of lack of the markers that would have delimitated
clearly the typical and atypical hyperplasia from a malignant tumor. The breast
carcinoma has been classified in subgroups being based on histological type and
grade [1, 2]. This tumor possesses many histological expressions diversified into
subgroups according to histological grade and receptors expression, which
indicates on the diverse etiology of these entities [3].
The morphological diversity of breast carcinoma fascinated the scientists
along the time. It has been defined 2 groups of breast carcinoma: in situ and
invasive. The difference between these types is represented by the integrity of
the basement membrane, in the case of invasive carcinoma the last one being
devastated by the tumor cells. In situ carcinoma includes the subtypes
comedo, cribriform, micropapillar, papillar, and solid.
Classic invasive forms, frequently diagnosed and studies, are: invasive
ductal carcinoma (50-80 %), NST type (of no special type) and lobular (5-15%)
[4, 5]. It is to be mentioned, that initially, these terms (ductal/lobular) were used
to identify the topographic origin of the neoplasm within the mammary
glandular system. The hypothesis according which the morphological types of
breast cancer originate from distinct microanatomic domains was contested by
Wellings et al. (1973, 1975), which demonstrated that broad variety of
mammary invasive carcinomas and their in situ precursors appear from the
terminal ductal/lobular unit, indifferent of histological type [6, 7]. Morphologically, the types of breast carcinoma are defined based on distinct
architectural pattern, cellular peculiarities and immunohistochemical profile.
Special types are determined in 25 %, and according to World Health
Organization data, are known at least 17 subtypes (ductal/lobular, tubular,
mucinos (coloid), medullar, papillary and their varieties) [4, 8].
Related to the age, Stalsberg et al. (1993) revealed that the incidence of
invasive ductal carcinoma is stable, frequency of papillary and mucinos
subtypes growth with the elderly, whereas the probability of papillary and
inflammatory forms decreases [9]. The incidence of lobular and tubular
218
carcinoma increase up to 50 years old, after which remains constant. A recent
correlation between the age and histological type has been shown by
Anderson et al. (2004), which determined that incidence of ductal, lobular,
tubular, mucinos and papillary carcinoma growths with age, whereas the
medullar and inflammatory forms approach their maximum at 50 years old
[10]. The highest rate of mortality is attested in inflammatory form, followed by
the ductal invasive one [11]. Related to the hormonal status, lobular,
ductal/lobular and mucinos carcinomas are ER+/PR+, and comedo ER-.
Ellis et al. considered that tubular, cribriform and mucinos forms have an
unfavorable prognostic [12]. Lobular carcinoma prognosis depends on the
subtype. Such, a mixed version, tubulo-lobular and invasive papillary
carcinoma are associated with a better overall prognosis than classic ductal
carcinoma [13]. At the same time, solid form of lobular carcinoma, invasive
ductal carcinoma and invasive carcinoma classic mixed lobular-ductal have a
poor prognosis. According to Jirstrom et al. (2005), more aggressive in
evolution in postmenopausal women are invasive ductal/lobular and lobular
[14]. Because of the fact that about 80% of cases are invasive ductal classics,
lobular typical 15% and 4% mixed, ductal-lobular indicates that in the majority,
the diagnosis of breast carcinoma has an unfavorable prognostic value for the
patient. Determination of histological type is recommended by multiple
specialty councils, which develops algorithms and processes of differentiation.
However, there are data that argue that differentiation into ductal and lobular
invasive type has no clinical value [15-17].
According to Fritz et al. (2010), although lobular type is more commonly
encountered in the elderly, and his tumor cells express with predilection
receptors ER and PR, compared to ductal invasive type, mostly Her2+, the
same author has refuted the hypothesis that the rate of local recurrences in the
lobular type is higher [18]. The absence of clinical impact in differentiation of
these two subtypes was demonstrated at the molecular level as well,
measuring metastatic potential by evaluating of E-cadherin and TFGb [19]. But
there are conflicting data that point out the enhanced ability of metastasizing of
lobular carcinoma due to CDH1 gene inactivation. In diagnostic purpose, the
absence of E-cadherin (encoded by CDH1) certifies lobular type of tumor [20].
Multicentric form of carcinoma, though correlates with nodal status, histologic
grade and tumor size, is not considered to be an independent prognostic factor
[21]. According to Cristofanilli et al. (2005), primary chemotherapy with
anthracyclines and taxanes is more effective in the lobular forms, but
resistance to tamoxifen is more expressed in lobular subtype ER+ than in
ductal ER+ [22].
Histological grade is an assessment of the degree of differentiation
(formation of tubular structures, nuclear pleomorphism) and proliferative
activity (mitotic index) of the tumor, actually considered by many an index of
cancer aggressiveness [4, 23]. In order to establishment the therapeutic
management, histological grade was incorporated into multiple algorithms,
such as NPI prognostic particularities (Nottingham Prognostic Index) and
Adjuvant! Online [24]. It has been established that histological grading has a
219
prognostic value in patients with G1 grade with an rate of survival much longer
than in G2 and G3 [1]. In accordance to Basler et al. (1984), the mean rate of
10 years survival is 45% for G1, G2-27 %, G3-18 % [25]. Correlating
histological grade with type has been determined that most commonly G3
meets in medullary carcinomas, comedo, inflammatory, whereas the tubular,
papillary, mucinous types are better differentiated and more rarely develop
metastases [11]. But the efficiency of the use of the histological scale is largely
restricted (28%) by the specialist’s experience [26].
One of the factors with major predicting significance is considered to be
the status regional lymph nodes. An argument in support of this factor is that,
the survival 10 years rate for patients with metastases in lymph nodes is 25-30
%, and in the absence of them is about 75%. Multiple studies have been
focused on the number of lymph nodes metastases, causing a reverse
correlation with survival rate [27].
Another important prognostic factor was determined to be vascular
invasion of the tumor [28]. It can be used as an independent predictive and
prognostic factor. The aggressive character of the tumor is determined by the
perineural invasion, while the detection of tumor necrosis predicts decreasing
survival period and involves resistance to treatment [29]. According to Rosen
et al. (1989), the rate of recurrences in the presence of vascular invasion
(blood and lymph) is higher (38 %) than in its absence (22 %) [30]. At the
same time, Neville et al. (1992) argues that the invasion of the lymphatic
vessels increases the recurrences by 15% within five years, in both groups,
with or without adjuvant therapy [31]. The data about the prognostic
significance of the fibrosis degree of the stroma in general and of elastosis in
particular have not found clinical application.
For oncological practice were defined 3 risk groups concerning the
possibility of postoperative recurrences and susceptibility to systemic therapy,
important in the selection of therapeutic tactics:
1. Reduced risk – patients older than 35 years, absence of metastases,
tumor size less than 2 cm, G1, Her2 negative, no vascular invasion. Hormonal
therapy is of first choice.
2. Intermediate risk – patients in which metastases were not found plus
one of the criteria: age <35 years old, tumor size >2 cm, G2-3, Her2 positive,
with vascular invasion. Another combination that defines this group is: 1-3
lymph nodes with metastases and primary tumor Her2 positive. Hormonal
therapy is preferentially indicated and if the response is unclear could be given
endocrine therapy +chemotherapy, or simply chemotherapy.
3. High risk – 1-3 lymph nodes with metastases and primary tumor is
Her2 negative or more than 4 affected lymph nodes. To this group of patients
is indicated chemotherapy+endocrine therapy, or only chemotherapy.
Paradoxically, but from all histological peculiarities of breast cancer are
used only histological grade of tumor differentiation, presence of vascular
invasion and of lymph node metastases [32].
Through the highlights of recent achievements, the unique widely
accepted histological factor with prognostic value is the grade of tumor
220
differentiation. G3 is a recommendation for chemotherapy [33]. Therefore,
nowadays there are many women whom toxic chemotherapy is prescribed and
who probably would feel better without the treatment, and many women in
which appear the recurrences in spite of the applied chemotherapy [34].
Management of patients with breast carcinoma is still guided by clinicpathological and morphological features. Although some schemes of treatment
seem to be effective, there is not yet enough potential to realize a personalized
therapy. The blind treatment of breast carcinoma, based rather on the
statistics, in which the classical histological aspect of the tumor has only
prognostic value, being valueless from the predictive point of view was the
reason for a complex studying of a broad spectrum of cellular markers.
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Гістологічне дослідження є "золотим стандартом" у визначенні діагнозу пухлинних захворювань. Рак молочної залози представлений морфологіч-ними
підвидами, які клінічно і гістологічно різноманітні, всупереч єдиному походженню.
Крім того, пухлини одного підвиду мають різне клінічний перебіг. Високою
неоднорідністю характеризується інвазивний протоковий рак, який є
лідером у структурі злоякісних захворювань молочної залози. Лікування
ґрунтується наі клінічних даних, таких як вік пацієнтки, лімфонодальний
статус, розмір пухлини, а також на гістологічних ознаках таких як ступінь
диференціації, морфологічний тип пухлини, лімфососудістая інвазія . Однак ці
дані не мають інтелектуальної цінності в розробці ефективного лікування
раку молочної залози.
Метою даного дослідження є оцінка предиктивного і прогностичного
потенціалу морфологічного діагнозу за раку молочної залози. Незважаючи на
те, що деякі схеми лікування здаються ефективними, їм не вистачає
потенціалу для індивідуального лікування. Лікування «в сліпу», засноване
скоріше на статистиці, ніж на індивідуальній чутливості пухлинних клітин до
застосовуваних препаратів, в якому морфологічна картина пухлинної маси
має лише прогностичне значення і не впливає на вибір лікувальної тактики,
підтверджує актуальність проведення досліджень клітинних маркерів за раку
молочної залози.
Рак молочної залози, морфологічна класифікація, предіктивний
потенціал, прогностична цінність
Гистологическое исследование является “золотым стандартом” в
постановлении диагноза опухолевых заболеваний. Рак молочной железы
представлен морфологическими подвидами, которые клинически и гистологически разнообразны, вопреки единому источнику. Кроме того, опухоли
одного подвида имеют разное клиническое течение. Высокой неоднороднос-
223
тью характеризуется инвазивный протоковый рак, который является
лидером в структуре злокачественных заболеваний молочной железы. Лечение
основывается на ряде клинических данных, таких как возраст пациентки,
лимфонодальный статус, размер опухоли, а также ряде гистологических признаков, таких как степень дифференциации, морфологический тип
опухоли, лимфососудистая инвазия. Однако эти данные не имеют
предиктивную ценность в разработке эффективного лечения рака молочной
железы. Целью данного обзора являлась оценка предиктивного и прогностического потенциала морфологического диагноза при раке молочной
железы. Несмотря на то, что некоторые схемы лечения кажутся эффективными, им не хватает потенциала для разработки индивидуального лечения.
Лечение «в слепую», основанное скорее на статистике, нежели на индивидуальной чувствительности опухолевых клеток к применяемым препара-там,
в котором морфологическая картина опухолевой массы имеет лишь
прогностическое значение и не влияет на выбор лечебной тактики, подтвердждает актуальность проведения исследований клеточных маркеров
при раке молочной железы.
Рак
молочной
железы,
морфологическая
классификация,
предиктивный потенциал, прогностическая ценность